PubMed Health⌕ Search

Biomedical subjects

B Dahlén

Publications and source records attributed to B Dahlén.

At least 19 recordsLinked to original sources
PubMed2006

Altered apoptosis in bronchoalveolar lavage lymphocytes after allergen exposure of atopic asthmatic subjects.

The increased number of lymphocytes in airways during an asthmatic response is believed to be the result of increased recruitment of these cells. However, it is possible that a decreased apoptotic rate could also contribute to the increased number. The aim of the present study was to investigate whether allergen airway provocation influences the apoptotic phenotype of lung and peripheral blood lymphocytes (PBL) in subjects with atopic asthma. Bronchoalveolar lavage (BAL) lymphocytes and PBL from 12 asthmatic subjects previously challenged with allergen (n = 7) or saline (n = 5) were exposed to the apoptotic stimulus tributyltin (TBT) in vitro and assayed for apoptosis. Airway allergen provocation resulted in decreased sensitivity of BAL lymphocytes to TBT-induced apoptosis, with 42.2% (range 33.9-62.5%) apoptotic cells before challenge versus 23.5% (range 15.3-42.4%) after challenge, while PBL were unaffected. The increased apoptosis resistance correlated with higher numbers of Bcl-2-expressing lymphocytes. Interestingly, baseline caspase-3-like activity was significantly elevated in viable BAL lymphocytes compared with viable PBL, and was unaltered by allergen exposure. In conclusion, allergen inhalation renders bronchoalveolar lavage lymphocytes more resistant to apoptosis while peripheral blood lymphocytes were not influenced at all, indicating that the apoptotic phenotype of airway lymphocytes may play a role in asthmatic inflammation.

Adult↗
PubMed2006

Early rise in exhaled nitric oxide and mast cell activation in repeated low-dose allergen challenge.

Repeated low-dose allergen inhalation challenge mimics natural allergen exposure, providing a model for early mechanisms in the triggering of asthma. The current authors performed a controlled study to evaluate the time course of changes in exhaled nitric oxide fraction (F(e,NO)) and urinary biomarkers of airway inflammation. Eight subjects with mild allergic asthma completed two 7-day repeated low-dose challenge periods, with diluent and allergen, respectively. Subjects were symptom free at inclusion and were investigated when not exposed to specific allergen. Pulmonary function and symptoms were followed, and F(e,NO) and urinary mediators were correlated to changes in airway responsiveness to histamine and adenosine. Despite no change in pulmonary function (forced expiratory volume in one second mean+/-sem fall 0.3+/-0.7 versus 0.6+/-1.0%, for diluent and allergen, respectively) and no asthma symptoms, repeated allergen exposure, in contrast to diluent, caused significant increases in histamine responsiveness (2.3 doubling doses), an early and gradual increase in F(e,NO) (up to a doubling from baseline) and a small increase in the mast cell marker 9alpha11beta-prostaglandin F(2) after adenosine challenge. In conclusion, serial measurements of exhaled nitric oxide fraction have the potential to provide a very sensitive strategy for early detection of emerging airway inflammation and subsequent changes in airway hyperresponsiveness to histamine.

Adenosine Monophosphate↗
PubMed2005

Relation between bronchial responsiveness to inhaled leukotriene D4 and markers of leukotriene biosynthesis.

BACKGROUND: While clinical trials with antileukotrienes have shown overall beneficial effects in asthma, the factors that determine leukotriene dependent asthma are still unclear. A study was undertaken to determine whether or not leukotriene responsiveness in the airways correlates with endogenous leukotriene biosynthesis. METHODS: Bronchial responsiveness to leukotriene (LT) D4 was assessed as PD20FEV1 in 20 subjects with mild asthma and 10 healthy controls, and compared with bronchial responsiveness to methacholine and two global measures of leukotriene production-urinary LTE4 and ex vivo production of LTB4 in whole blood. RESULTS: In patients with asthma the bronchoconstrictor activity of LTD4 was about 1300 times greater than methacholine (geometric mean PD20 0.69 nmol v 887 nmol). Those who were most responsive to LTD4 were relatively less responsive to methacholine (p<0.01). There was, however, no correlation between bronchial responsiveness to LTD4 and urinary LTE4 or blood ex vivo LTB4 levels in asthmatic subjects or healthy controls. Subjects with asthma treated with inhaled corticosteroids produced higher levels of LTB4 (p<0.05). CONCLUSIONS: General measures of leukotriene production cannot predict bronchial responsiveness to LTD4. The unique bronchoconstrictive potency of LTD4 on human airways may relate to the locally regulated expression of the cysteinyl LT1 receptor.

Adult↗
PubMed2005

Leukotriene D4-induced hypoxaemia in asthma is mediated by the cys-leukotriene1 receptor.

Bronchoprovocation with cysteinyl-leukotrienes (LTs) induces airflow obstruction and gas exchange abnormalities, namely ventilation-perfusion ratio (V'(A)/Q') imbalance. However, it is unknown which of the two different receptors for cysteinyl-LTs mediate these V'(A)/Q' disturbances. In a double-blinded, crossover design, 10 patients with mild asthma were randomised to receive an oral single dose of the selective cysteinyl-LT1 receptor antagonist montelukast (40 mg) or placebo before leukotriene (LT)D4 inhalation challenge. Gas exchange, including V'(A)/Q' descriptors were measured at baseline, 3 h after montelukast/placebo pretreatment and 5, 15 and 45 min after the LTD4 challenge. Compared with montelukast, inhalation of LTD(4) induced a marked fall in forced expiratory volume in one second (mean+/-se 33+/-2%) and profound V'(A)/Q' mismatching, reflected by a decreased arterial oxygen tension (from 100+/-4 to 75+/-3 mmHg) and an increased overall index of V'(A)/Q' heterogeneity dispersion of retention minus excretion inert gases corrected for dead space (from 4.9+/-1.2 to 8.4+/-1.1; normal< or =3.0; dimensionless), 5 min after placebo. Following montelukast, LTD4 produced no significant changes in any of the variables. In conclusion, these findings point to the view that leukotriene D4)-induced gas exchange disturbances and bronchoconstriction are both mediated by the cysteinyl-leukotriene1 receptor.

Acetates↗
PubMed2003

Indirect airway challenges.

Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle. Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma, e.g. exercise-induced bronchoconstriction, evaluation before scuba diving. Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges, e.g. hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.

Asthma↗
PubMed2001

Pulmonary gas exchange and sputum cellular responses to inhaled leukotriene D(4) in asthma.

Inhalational challenges with inflammatory mediators may provoke lung function disturbances similar to those shown in spontaneous acute asthma. Cysteinyl leukotrienes (CysLTs) have recently been established as mediators of bronchoconstriction in asthma but their effects on pulmonary gas exchange in asthma have not been assessed. We therefore investigated the effects of leukotriene D(4) (LTD(4)) challenge resulting in a significant decrease in FEV(1) (mean +/- SE, by 32 +/- 3%) in 13 nonsmoking, mild asthmatics. Respiratory system resistance (Rrs), and respiratory and inert gases were measured before and immediately after, and at 15 and 45 min after challenge. After bronchoprovocation, Rrs increased (by 106 +/- 12%), Pa(O(2)) decreased (by 25 +/- 4 mm Hg), and ventilation-perfusion distributions moderately to severely deteriorated, as shown by increases in the dispersions of pulmonary blood flow (Log SDQ, by 59 +/- 12%) and alveolar ventilation (Log SDV, by 65 +/- 20%) (p < 0.05 each). Sputum eosinophils (p < 0.05) and urinary LTE(4) (p < 0.005) increased after challenge. Despite the lack of mathematical correlations between spirometric and Rrs changes and gas exchange indices, the pattern of improvement of the functional variables after challenge ran in parallel. These findings support the evidence that CysLTs, in addition to being potent bronchoconstrictors, also provoke profound disturbances of pulmonary gas exchange in asthma.

Administration, Inhalation↗
PubMed2001

Cytokine mRNA expression in patients with mild allergic asthma following low dose or cumulative dose allergen provocation.

BACKGROUND: Allergen provocation is a very useful way to study the inflammatory response in asthmatic patients. Although cumulative dose regimens are most often applied, another provocation model with repeated inhalations of low doses of allergens has recently come into use. OBJECTIVE: We were interested to compare these two allergen provocation models. To evaluate the inflammation induced by either model, we examined the mRNA expression of several cytokines that are implicated in the orchestration of the inflammatory response observed in asthma. METHODS: Interleukin (IL)-4, IL-5, IL-13 and interferon (IFN)-gamma mRNA expression was analysed in bronchoalveolar lavage (BAL) cells and peripheral blood (PB) CD4+ and PB CD8+ T cells following any of the two provocation regimens. IL-4 and IFN-gamma mRNA expression was analysed by a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) method, while IL-5 and IL-13 were analysed semiquantitatively, before and after allergen provocation with either model. RESULTS: After low dose provocations none of the cell populations studied showed a clear change in the pattern of IL-4 or IFN-gamma gene expression. In contrast, after cumulative dose provocation there was a clear tendency towards an increased IL-4 mRNA expression in BAL cells, correlating with a significant increase in IL-4 mRNA in PB CD4+ as well as in CD8+ T cells (P = 0.005 and P = 0.04, respectively). Regardless of the allergen provocation method used, in PB IL-4 mRNA was preferentially expressed by CD4+ cells while IFN-gamma was expressed more by CD8+ cells. IL-5 transcripts increased after low dose provocations in PB CD4+ T cells in six of eight patients, while after cumulative dose provocation IL-5 mRNA increased in BAL cells in six out of nine patients but decreased especially in PB CD8+ T cells in six out of eleven patients, suggesting an accumulation of IL-5 expressing cells to the lungs. CONCLUSION: Thus, the cumulative dose provocation regimen can induce a more pronounced Th2-like immune response in asthmatic patients than the low dose provocation model.

Adult↗
PubMed2001

The reproducibility and sample size requirements of exercise-induced bronchoconstriction measurements.

Dry air exercise challenges are frequently used to screen medications that have potential utility in the management of exercise-induced bronchoconstriction (EIB). The purpose of this study was to determine the reproducibility of three outcome measurements made using such challenges, and sample size requirements for drug evaluation studies based on these outcomes. Forty adult subjects with asthma, who tested positively on a screening exercise challenge, were subjected to two further identical challenges, separated by 1 to >35 days. Outcome measurements included the maximum per cent fall in forced expiratory volume in one second (FEV1), after exercise (% fallmax), and the area under the per cent fall in FEV1/time curve for 30 min (AUC30) and 60 min (AUC60) after exercise. The reproducibility of these outcomes, as assessed by intraclass correlation coefficients was 0.72, 0.53 and 0.35 for % fallmax, AUC30 and AUC60 measurements, respectively. The sample size requirements to demonstrate an attenuation of EIB equivalent to a 50% reduction in % fallmax was 9, 14 and 19 subjects for the % fallmax, AUC30 and AUC60 responses, respectively (90% power). It is concluded that the maximum percentage fall in forced expiratory volume in one second has greater reproducibility and results in greater power in clinical trials than area under the curve measurements. Sample size calculation curves are provided which may be used in study design and interpretation of published studies.

Adult↗
PubMed2000

The challenge procedure influences the extent of allergen-induced urinary excretion of leukotriene E4.

BACKGROUND: Cysteinyl-leukotrienes are central mediators in asthma and urinary leukotriene E4 (LTE4) is a reliable marker of their endogenous formation. OBJECTIVE: This study tested the hypothesis that the procedure used for allergen bronchoprovocation influences the bronchoconstrictor response and the amount of LTE4 excreted following allergen challenge. METHODS: Seven atopic asthmatic men underwent two allergen bronchoprovocations 4 weeks apart. The same total dose of allergen was given at both sessions, cumulatively on one occasion and as a single dose at the other session. Urine was collected in hourly samples before and after challenge and LTE4 was measured with previously validated methodology. RESULTS: The mean (+/- SE) drop in FEV1 was not significantly different between the cumulative (29 +/- 2.4%) and the single dose challenge (25 +/- 2.8%). There was a significant increase in post-challenge levels of urinary LTE4 after both sessions. The peak excretion of LTE4 occurred 1 h following the maximal drop in FEV1 for both challenges. However, the post-challenge increase in urinary LTE4 was significantly larger at the cumulative session. In fact, the net increase (post-challenge minus prechallenge) of urinary LTE4 was more than twofold higher after the cumulative session (AUC 0-3 h post-challenge: 46.7 +/- 8.2 vs 22.1 +/- 9.8, P < 0.05). CONCLUSION: The peak excretion of urinary LTE4 occurred within 2 h after the termination of either challenge but the magnitude of urinary excretion of LTE4 was larger when cumulative challenge was performed. The findings are important to consider when designing studies where allergen-induced urinary excretion of LTE4 is an outcome variable.

Adult↗
PubMed1999

Airway inflammation and altered alveolar macrophage phenotype pattern after repeated low-dose allergen exposure of atopic asthmatic subjects.

BACKGROUND: The alveolar macrophage (AM) constitutes an important link between pulmonary innate and adaptive immunity due to its antigen-presenting capacity and ability to express different immunomodulating mediators. The role of AMs in the pathogenesis of allergic inflammation has yet to be fully determined. OBJECTIVE: To investigate clinical effects and any change in the AM phenotype pattern after inhalation of sub-clinical doses of allergen by asthmatic patients. METHODS: Eight subjects with allergic asthma underwent repeated low-dose allergen provocations equivalent to 10% of PD20. AMs recovered with bronchoalveolar lavage (BAL) were characterized by flow cytometric analysis of adhesion molecules, co-stimulatory molecules and markers for AM population activation and heterogeneity. RESULTS: An allergic airway inflammation, sub-clinical in six out of eight subjects, was obtained after low-dose allergen provocations, as determined by increased airway methacholine reactivity, increased BAL fluid total cell and eosinophil counts and increased serum ECP levels. The AMs showed a post-challenge altered phenotype pattern with a decreased expression of CD11a, CD16, CD71 and HLA class I and an increased expression of CD11b and CD14. The AMs were positive for CD83 and a weak post-challenge increase in the CD83 expression was found. CONCLUSION: Repeated low-dose allergen exposure induces an allergic airway inflammation in asthmatic subjects. The inflammation is associated with an altered AM phenotype pattern, consistent with an influx of monocytes and a hypothetical increased accessory cell function in the airways, possibly contributing to the development and sustenance of airway inflammation in asthma.

Adult↗
PubMed1998

Urinary excretion of inflammatory mediators during allergen-induced early and late phase asthmatic reactions.

BACKGROUND: It is generally accepted that the early asthmatic response to inhaled allergen is a result of IgE-mediated mast cell activation. In contrast, the underlying mechanism of the late asthmatic response is much less clear. OBJECTIVE: In order to investigate the pattern of mediator release during the early and late asthmatic responses to allergen, measurements of the urinary excretion of the mast cell markers 9alpha,11beta-PGF2 and Ntau-methylhistamine were made. In addition, urinary levels of eosinophil protein X (EPX) and leukotriene E4 (LTE4) were measured. METHODS: Twelve mild atopic asthmatics participated in the study. On the study day, pulmonary function was recorded at baseline and for 12 h after inhalation of allergen. Urine was collected prior to challenge and thereafter at 1 h intervals. Measurements of 9alpha, 11beta-PGF2 and LTE4 were made with enzyme-immunoassay, and levels of Ntau-methylhistamine and EPX were analysed with radioimmunoassay. RESULTS: All subjects developed both an early and late phase airway response. Within 1 h of the early peak airway response, there was a significant increase in the urinary concentrations (AUC/h) of 9alpha, 11beta-PGF2 (49.3 +/- 9.2 to 142.5 +/- 49.2; P < 0.001) Ntau-methylhistamine (10.4 +/- 1.4 to 19.5 +/- 1.4; P < 0.001) and LTE4 (43.7 +/- 5.9 to 105.9 +/- 21.3; P < 0.001). Levels of all three mediators were also significantly increased above baseline during the LAR to 79.4 +/- 9.5 (P < 0.01), 19.8 +/- 1.9 (P < 0.001) and 85.6 +/- 10.4 (P < 0.001), respectively. Levels of EPX remained unchanged during the early and late responses (39.2 +/- 10.2 to 37.5 +/- 18.5, 33.9 +/- 6.8). CONCLUSIONS: These results indicate that mast cell activation is a feature not only of the early but also the late asthmatic response. Finally, increased LTE4 supports the contribution of the leukotrienes to airway obstruction during both phases of the asthmatic response to allergen.

Adolescent↗
PubMed1998

Selective CD8+ T cells accumulate in the lungs of patients with allergic asthma after allergen bronchoprovocation.

Our objective was to study whether CD4+ or CD8+ T cells expressing particular T cell receptors (TCR) would accumulate in the lungs of patients with allergic asthma following allergen exposure. We thus analysed the TCR Valpha and Vbeta gene usage of CD4+ and CD8+ lung and peripheral blood lymphocytes (PBL) of eight patients with allergic asthma before and 4 days after inhalation challenge with the relevant allergen. Lung cells obtained by bronchoalveolar lavage (BAL) and paired PBL samples were analysed by flow cytometry using a panel of anti-TCR V-specific monoclonal antibodies that encompass = 50% of the T cell repertoire. Lung-limited T cell expansions were recorded in both the CD4+ and the CD8+ subsets. In BAL CD8+, out of a total of 126 analyses, the number of T cell expansions increased from two to 11 after challenge, some of them dramatic. In BAL CD4+ the frequency of expansions was moderately increased already before challenge, but remained unchanged. A few expansions that tended to persist were noted in PBL CD8+. When analysing the overall change in TCR V gene usage the largest changes were also recorded in the BAL CD8+ subset. Specific interactions between T cells and antigens may lead to an increased frequency of T cells using selected TCR V gene segments. In this study we demonstrate that following allergen bronchoprovocation in allergic asthmatic subjects, T cell expansions preferentially emerge in the lung CD8+ T cell subset.

Adult↗
PubMed1998

Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics.

From bronchoprovocation studies and investigations of the acute effects of drugs that inhibit leukotrienes (LT), the hypothesis has emerged that leukotrienes are important mediators of airway obstruction and other symptoms in aspirin-intolerant asthma (AIA). However, it has yet not been shown if subjects with AIA respond favorably to clinical treatment with leukotriene inhibitors. Therefore, in a double-blind placebo-controlled crossover study, we examined the effects of 6 wk of treatment with the leukotriene-pathway inhibitor zileuton (600 mg, four times daily) in 40 patients with well-characterized AIA. The treatment was added to existing therapy, which included medium to high doses of inhaled (average daily dose 1,030 microg of beclomethasone or budesonide) or oral glucocorticosteroids (4 to 25 mg/d) for all but one of the patients. On top of this treated baseline, there were no significant effects of adding placebo, indicating that their asthma was kept relatively stable. However, there was an acute and chronic improvement in pulmonary function after treatment with zileuton, expressed both as increased FEV1 from baseline compared with placebo, and higher morning and evening peak expiratory flow rate (PEFR) values on zileuton treatment compared with placebo. The improvements occurred despite lower use of rescue bronchodilator with zileuton. Zileuton also diminished nasal dysfunction, which is one of the cardinal signs of AIA. There was a remarkable return of smell, less rhinorrhea, and a trend for less stuffiness and higher nasal inspiratory flow during treatment with zileuton. Zileuton caused a small but distinct reduction of bronchial hyperresponsiveness to histamine and inhibited aspirin-induced bronchoconstriction. Zileuton inhibited urinary excretion of LTE4 but did not change airway reactivity to inhaled LTD4, supporting that zileuton specifically inhibited leukotriene biosynthesis. The findings indicate that leukotrienes are important mediators of persistent airway obstruction and chronic nasal dysfunction in AIA. The study also suggests that addition of a leukotriene pathway inhibitor such as zileuton may bring about greater control of asthma than what is achieved by treatment with medium to high doses of glucocorticosteroids alone.

Adrenergic beta-Agonists↗
PubMed1998

Evidence for mast cell activation during exercise-induced bronchoconstriction.

Controversy remains about the causative mediators in the bronchoconstrictive response to exercise in asthma. This study examined whether mast cell activation is a feature of exercise-induced bronchoconstriction by measuring urinary metabolites of mast cell mediators. Twelve nonsmoking subjects with mild asthma and a history of exercise-induced bronchoconstriction exercised on a stationary bicycle ergometer for 5 min at 80% maximum work load. Pulmonary function was monitored and urine was collected before and 30 and 90 min after the provocation. The urinary concentrations of the mast cell markers 9alpha,11beta-prostaglandin (PG)F2 and Ntau-methylhistamine, as well as leukotriene E4 (LTE4) were determined by immunoassay. Seven of the 12 subjects (responders) experienced bronchoconstriction (>15% fall in the forced expiratory volume in one second) following exercise, whereas the pulmonary function of the remaining five subjects (nonresponders) remained stable. The urinary excretion (mean+/-SE) of 9alpha,11beta-PGF2 in the responders increased significantly compared with the nonresponders at 30 (77.1+/-14.4 versus 37.2+/-5.6; p<0.05) and 90 min (79.3+/-8.6 versus 40.4+/-8.5, p<0.05) after exercise challenge. The urinary excretion of Ntau-methylhistamine and LTE4 was not significantly different between the two groups at 30 or 90 min after exercise. The findings represent the first documentation of increased urinary levels of 9alpha,11beta-prostaglandin F2 in adults following exercise challenge and provides clear evidence for mast cell activation during exercise-induced bronchoconstriction in asthmatics.

Adult↗